Bacteria have the ability to generate resistance to antibiotics through lateral gene transfer, mutation of enzymes, or the expression of enzymes which actively pump the antibiotic out of the cell or break it down. Over the past 10 years, resistance to existing antibiotics has become a significant problem in many countries. Vancomycin is currently the drug of last resort to combat multidrug-resistant Gram-positive bacteria. In many places vancomycin-resistant Staphylococcus aureus and Enterococci (VRE) have been discovered. There is thus a desperate need for a new antibiotic drug to replace this drug of last resort.
There are a host of cytoplasmic targets for the development of new antibacterials, such as gyrase inhibitors, protein synthesis inhibitors, muramyl cascade inhibitors, and many more. The major hurdle in designing such drugs is that in addition to enzyme based activity these drugs need to cross the bacterial cell wall to exert their antibacterial effect. On the other hand, enzymes involved in synthesis of the bacterial cell wall exist on the cell wall exterior, and therefore drugs inhibiting these enzymes can exert their bactericidal or bacteriostatic effect without having to cross the cell wall. For example, penicillins, cephalosporins, and vancomycin are antibiotics that interact with bacterial transpeptidase enzymes. In particular, moenomycin A is an antibiotic which binds to bacterial transglycolsylase enzymes. Each of these antibiotics either controls and/or inhibits peptidoglycan biosynthesis in bacteria, and each exerts its effect without having to cross the bacterial cell wall.

On a molar basis, moenomycin A is a thousand times more potent than vancomycin, but its absorption upon oral administration is relatively poor (van Heijenoort, Glycobiology (2001) 11:25R-36R). Structure-activity relationship studies of moneomycin analogs conducted on the sugar portion of the molecule have revealed that moenomycin analogs with at least three carbohydrate units (C, E, and F) are active in vivo against Gram-positive bacteria (for example, see Garneau et al., Bioorganic & Medicinal Chemistry (2004) 12:6473-6494, and references cited therein; each of which is incorporated herein by reference). However, to date, there has not been a comprehensive, systematic structure-activity relationship study of the entire moenomycin A structure.